Atrial fibrillation (AF) is the most prevalent arrhythmia, the incidence of which increases with age. It is estimated that 8% of all people over the age of 80 experience this type of abnormal heart rhythm and AF accounts for one-third of hospital admissions for cardiac rhythm disturbances. Over 2.2 million people are believed to have AF in the Unites States alone. Fuster et al Circulation 2006 114 (7): e257-354. Although atrial fibrillation is often asymptomatic it may cause palpitations or chest pain. Prolonged atrial fibrillation often results in the development of congestive heart failure and/or stroke. Heart failure develops as the heart attempts to compensate for the reduced cardiac efficiency while stroke may occur when thrombi form in the atria, pass into the blood stream and lodge in the brain. Pulmonary emboli may also develop in this manner.
Current methods for treating AF include electric and/or chemical cardioversion and laser ablation. Anticoagulants, such as warfarin, dabigatran, and heparin, are typically prescribed in order to avoid stroke. While there is currently some debate regarding the choice between rate and rhythm control, see Roy et al. N Engl J Med 2008 358:25; 2667-2677, rate control is typically achieved by the use of beta blockers, cardiac glycosides, and calcium channel blockers.
One of the most common anti-arrhythmic agents is amiodarone which is commonly administered for both acute and chronic arrhythmias, including acute and/or chronic AF. Unfortunately, amiodarone is a highly toxic drug and has a wide range of undesirable side effects. The most dangerous of these effects is the development of interstitial lung disease. Thyroid toxicity, both hypothyroidism and hyperthyroidism, is often seen, as are effects in the eye and liver. Additionally, many patients (8-18%) discontinue use of amiodarone after one year due to intolerant side effects.
Dronedarone, a non-iodinated derivative of amiodarone, reduces cardiovascular hospitalization and mortality in patients with atrial fibrillation and/or atrial flutter (AFL), but its anti-AF efficacy in the clinic is inferior to that of amiodarone.2,3 After several large trials,4-8 the Unites States Food and Drug Administration (FDA) approved dronedarone (400 mg BID) in July of 2009 for the reduction of risk of cardiovascular hospitalization in patients with paroxysmal or persistent AF or AFL. In the clinical studies, doses of dronedarone 400, 600, or 800 mg twice daily (BID) were studies in patients with AF/AFL. Dronedarone 400 mg BID was associated with significant reduction in the risk of recurrent atrial fibrillation, but doses of dronedarone 600 mg BID and 800 mg BID were not effective and were poorly tolerated. Thus, methods of increasing the anti-arrhythmic efficacy of dronedarone are highly desirable.
It has now been found that the combination of dronedarone and ranolazine has synergism resulting in potent electrophysiologic actions leading to marked suppression of atrial arrhythmias among other cardiac conditions. For example, the combination of dronedarone and ranolazine has synergism in reducing AV nodal conduction and ventricular tachyarrhythmia.